Leptospirosis, a zoonotic spirochaetal disease with worldwide distribution, is an emerging infectious disease. We have shown that leptospirosis has now spread from its traditional rural base to become the cause of cyclic rainfall-associated epidemics in the urban setting. Conditions of climate and growing urban poverty have contributed to the emergence of this new epidemiological pattern: large outbreaks associated with high mortality occur each year during the same seasonal period and affect the same risk groups within urban slum communities. The public health priority in response to these epidemics is to address the severe clinical forms, such as Weil's disease and severe pulmonary haemorrhage syndrome, for which mortality is >15 percent. Current treatment and control measures have not made an impact in reducing this mortality and therefore, new preventative approaches need to be developed. However, little is known regarding why a small proportion (5-15 percent) of individuals progress to develop severe clinical outcomes. We hypothesize that that in high transmission settings, severe clinical outcomes are influenced by differences in the inoculum size during exposure to environmental factors and by acquired immune response after natural infection. In the city of Salvador, Brazil, we have established the epidemiological and laboratory infrastructure to study leptospirosis. Five-year surveillance at this site has identified more than 1400 severe leptospirosis cases, therefore providing a unique opportunity to study the natural history of leptospirosis. We propose a community-based longitudinal study that aims to: (1) Determine whether environmental risk exposures, including those that may influence inoculum size during infection, are associated with an increased risk of developing severe disease after infection, and (2) Determine prospectively whether immunological responses, acquired during a prior infection, protect against re-infection with pathogenic Leptospira. These studies should identify potential preventative measures for severe leptospirosis. At the same time, they may provide more widely applicable benefits such as the development of improved diagnostic tools and identification of targets for vaccine development.